Phenyl-azo-alpha-alpha-diamino-pyridine dihydrochlorides and method of obtaining the same



Patented Aug. 7, 1 928.

UNITED STATES PATEN IWAN OSTROMISLENSKY, OF NEWPHENYL-AZO-ALPHAeALPHA-DIAMINO-PYRIDINE DIHYDROCHLORIDES AND METHODYORK, N. Y., ASSIGNOR TO THE PYRIDIUM COB- PORATION, or NEW YORK, N. Y.,

A CORPORATION on NEW YORK.

or OBTAINING THE SAME.

No Drawing.

This invention is an improvement in methods of obtainingphenyl-azo-alphaalpha-diaminopyridines, and more particularly in methodsof obtaining the dl-hydrochlorides.

Formerly it was believed that alpha-alphadiaminopyridine functioned as amono-am base, inspite of the fact that its molecule contains threenitrogen atoms. It Was believed that two of the nitrogen atoms hadpresumably lost their basic properties. Ch chibabin succeeded inseparating, under various conditions, only mono-hydrochloride'ofdiaminopyridine. He also considered that the molecule of sulphuric acidbinds two molecules of alpha-alpha-diaminopyridine.

Notwithstanding all his eliorts, Ghichibabin was unable to obtain eitherthe salts or the nearest derivatives of alpha-alphadiaminopyridine as adi- .or tr1-ac1d base. Thus, for instance accordin to Qh1ch1bab1n,thephenyl-azo-alp a-alphaiaminopyridme, melting point 137. C., under theaction of hydrochlorlc or picrlc acid, only mono-hydrochloride, ormonopicrate.

It is sulphuric acid .which in every in stance binds the two moleculesof phenylazo-diaminopyridine. On the strength of numerous observationsmade by Chlchibabin in the course of several years, it was generallyaccepted in the literature that only one of the three atoms present "inthe alphaalpha-diaminopyridine molecule displays basic propertiespeculiar. to pyridine compounds. Accordlng to Chichibabin thesepeculiarities constitute a sharp demarcation line between the amines ofthe pyridine and those of the aromatic series, and in particular betweendiaminopyridlnes and phen'yL In his. book Investigations en'e-diamines.1918, Moscow Chichlin Pyridine Bases, ham among mentions the following:Of the three'nitrogen atoms in diaminopyridine and its derivalays basicproperties.

tives, one alone dis J lbabms observations I Contrary to Ohio was ableto show that phenyl-azo-alphaalpha-diaminopyridine functions not only'as a mono-acid but likewise as a di-acld base. Chemically purephenyl-azo-alpha-alpha-dlaminopyridine dihydrochloride, which Isueceeded n separating ofi, comes 1n the form invariably forms thefundamental deductions Application filed September 23, 1927. Serial Nor221,629.

thus unable to discover the existence of these 4 salts. As concentratedand even 6% hydrochlor c acid does not decompose dihydrochloride, thecompound. is easily produced by means of simple copulation of diazotizedaniline with alpha-alpha-diaminopyridine, of course provided thesolutions of these substances be sufiiciently concentrated and contain asufficient amount of hydrochloric acid (not less than 6%).

My method of obtaining phenyl-azo-alphaalpha-diaminopyridinedihydrochloride considerably facilitates and s1mplifies the r0- cedureof separatingofi the correspon ing' mono-hydrochloride, i. e. pyridium.The product resulting from the copulation process is separated oifdirectly in chemically pure condition and in the'form of theabovementioned characteristic prisms. As this substance displays highspecific gravity, it

precipitates readily in the container in which the reaction isconducted. As distinguished from almost amorphous micro-crystallinemono-hydrochloride (pyridium) in powder form, which displays colloidalproperties, it

is easily and very rapidly filtered under pressure and is likewise veryeasily separated ofi from its mother liquor on a centrifuge; the residuewhichit has adsorbed being easily removed by washing the substance in aweak, say l0%, solution of hydrochloric acid.

The mixture of beta and gamma isomers ofphenyl-azo-alpha-alpha-diaminopyridine monohy'di'ochloride, calledpyridium may be obtained by pourin temperature over the 'dihydrochlorideafter it has been purified in the above described distilled water atroom dine and aniline'hydrochloride. 66

way. In this process the dihydrochloride immediately and quantitativelysplits oil the molecule of hydrochloric acid and is thus converted tochemically pure monohydrochloride, i. e. pyridium. The latter substanceis then separated off either by centrifuging or by filtration underpressure-and washed in a small amount of ice Water and dried to constantweight in a temperature of 40-60 C. This new method of separating themono-hydrochloride enables the elimination of rccrystallizing the crudeproduct from cold water, which entails considerable loss of thesubstance.

Ewample I 5191.28 gms. of freshly-distilled aniline are dissolved in amixture of 14 litres of 37% hydrochloric acid and 24 litres of distilledwater. About 10 kilograms of ice must then be added to the solution. Thediazotization process is conducted by means of a solution of 3798 gins.of 90% sodium nitrite in 30 litres of water at 12 C. ap proximately. Ofcourse the process is checked with iodo-starch paper. When thediazotization is completed a solution of 6000 gms. ofalpha-alpha-diaminopyridine in 30 litres of 20% hydrochloric acid isadded at one time into the product obtained I found by experience thatthe temperature of the freshly-prepared mixture should not be allowed tofall below 12 G. However, the inost favorable temperature for thisreaction is 16- to 18 0. Only at this relatively high temperature afterdiazotization does the mixture, when it has been allowed to .stand forsome 30-120 minutes, give a copious sediment of phenyl-azo-alphaalphadiaminopyridine di-hydrochloride, (the beta and gamma isomers); itprecipitates rapidly to the bottom of the earthen- Ware or orcelaincontainer in which the reaction is conducted. This sediment is firstseparated off on a centrifuge Whose surface must be covered withbakelite or any other acid-proof varnish and then washed in 10%hydrochloric acid and dried with air in a drying closet to constantweight at 3045- 0.

Properties of the dihydrochlofide.

As distinguished from the mono-hydrochloride the substance which isobtained in the above-described way, dissolves very readily in coldpyridine; the solution is deep red in color. Consequently, the basicropcrties are more pronounced in pheny -azoalpha-alpha-diaminopyridinethan in pyridine. On the other hand, solutions made with cold anilineare yellow in color with a slight reddish tint. Most likely thesesolutions contain free phenyl-azo-diaminopyri- This substancedissolveseasily in methyl and ethyl alcohol; in benzene and anhydrousacetone it is almost insoluble; when boiled with benzol- (83 C.) itretains both its crystalline form and its glitter. In conti-adistinctionto the mono-hydrochloride, the dihydrochloride dissolves very rapidly inlukewarm water. But even if cold water is poured over it, it immediatelyloses its glitter and crystalline form, and is converted tomono-hydrochloride, i. e. pyridium. As distinguished from the aqueoussolutions of the mono-hydrochloride, the dihydrochloride solutions showa distinct acid reaction to Congo paper.

Under the action of ammonia, dihydrochloride -in' powder formimmediately changes its violet red color to a golden yellow'and istransformed to free phenyl-azodiaminopyridines which melt at 139 C.after a triple recrystallization from boiling water.

Concentrated and even 6% hydrochloric acid does not produce any actionon dihydrochloride, but it decomposes partially under the action of 45%hydrochloric acid, forming the mono-hydrochloride. A part of theoriginal crystals remain unchanged in this reaction. 3% hydrochloricacid decomposes dihydrochloride to the mono-h drochloride and freehydrochloric acid. he reaction takes place gradually but quantitative]It takes three da s to be completed, I i heated in a test tube in an oilbath, chemically pure dihydrochloride at ISO-210 C. splits ofl onemolecule of hydrochloric acid and is converted to themono-hydrochloride. In this-reaction the original dih drochloridecrystals lose their glitter. and ecome dull,

although retaining their original shape( The resulting product(pyridium) yields perfectly neutral solutions. with boiling water. I

In this heating process (180210 C.) dihydrochloride splits off itsrecrystallization Water which can be collected in a container and theamount of hydrochloric acid split oil: can be ascertained by means ofs1lver n1trate. Under the same conditions pyridium (180-210 C.) gives nowater at all and splits off only a negligible quantity of hydrogenchloride in traces. If heated 1n a capillary tube over a slow fire,dihydrochloride begins to split off hydrochloric acid perceptibly onlyat 180 C. The complete decomposition and coagulation temperatures forboth compounds (i. e. monoand dihydrochloride) in the process of heatingin a capillary tube, lie around 220224 C.

If desired, this dihydrochloride may be obtained in chemically purecondition by meansof a reaction conducted under certain conditlonsbetween hydrochloric acid and prepared mono-hydrochloride. In thisprocess the temperature as well as the concentration of themono-hydrochloride and hydrochloric acid in the original solution are ofthe greatest importance.

E sample [1.

' NH: Diazo-amido-compound is' not reversible.

Consequently, the new substance which I succeeded in separating oii'must without doubt-display the structure of aphenyl-azoalpha-alpha-diaminopyridine dihydrochloride. 7

As has already been mentioned in the text of the present application thenew compound which I separated ott' facilitates and reduces the cost ofthe process of obtaining mono-hydrochlorides, that is pyridium, asalready described by me, to quite a considerable extent. The procedureof obtaining the monohydrochloride from the dihydrochloride is asfollows: I

' Ewwmple HI.

Into 3 kilograms of dihy-drochloride placed in an earthenware container,70-100 litres of distilled water are added at normal temperature, theresulting mixture is then vigorously mixed for 10-30 minutes andfiltered oil under pressure or by centrifuging. The chemically .pure'mono-hydrochloride which is obtained by this process is washed in asmall amount of distilled water and then dried in air the temperature ofwhich is regulated in any suitable inanner to constant weight'at 30l555C. If handled with water in the proper way the resulting product willgive perfectly neutral solutions. The mother liquor and washing wa tors,which remain after themono-hydrochloride has been separated oil, may betreated with ammonia, and the pyridium base, that is, the beta and gammaisomers of phenyl-azo-alpha-alpha-diamino-pyridine that appears in thisreaction is carefully filtered oft and washed in large quantities ofdistilled water, then drained and converted to mono-hydrochloride byrecrystallizing it out of 3% hydrochloric acid. The total yield ofmono-hydrochloride dihydrochloride, as described in Example II, showsthat the substance which I have separated off and am describing in thepresent application cannot display the structure of the correspondingdihydrochloride of the diaZo-amido compound For though the conversion"of the said diazo-amido compound to an azo-amine compound (pyridium) isvery easily performed, as described in my application Serial No.-221,628, of even date herewith, namely just by heating it with water,yet the conversion of the azo-amido compound back to the diazo-amido onecannot actually be done. The reaction:

H2N/N Azo-amino-eompound reaches as high as 99.3% of the theory.

A closer investigation of the mono-hydrochloride obtained as describedin Example III shows, that whilst being but slightly toxic it displaysvery strong bactericidal properties. It dissolves quite easily inboiling water and the l to 2.5% aqueous saturated solutions made with itdisplay considerable stability. In all its chemical, physical,biochemical, biological, bacteriological and therapeutic properties andconstants this product is identical with the substance termed pyridium.

The behavior of aniline homoloeues and analogues, such as phenetidine,anisidine,

toluidine, in copulation with alpha-alphadiaminopyridine is analogouswith that of aniline itself. In this connection we shall not touch uponthe question of the formation of the isomeric forms (beta and gamma). Ihave merely observedthat under the same conditions these amines producethe dihydiochloride of the correspondingaryl-azoalpha-alpha-diaminopyridines. In turn these dihydrocl'iloridesare converted by treatment with water to the correspondingmono-hydrochlorides.

.My experience, however, has shown that among its analogues andhomologues pyridiumv itself. whilst displaying the lowest toxicity,produces the strongest bactericidal action. Moreover, pyridium di solvesin water much more readily.

, The dihydrochloride of phenyl-azo-alphaalpha-diaminopyridine asdescribed in this application, and the existence of which could not beforetold a priori, presentsv a certain interest for the followingreasons p 1. By means of the given dihydrochloride, themonohydrochloride of plienyl-azo-alphaalpha-diaminopyridine, that is,pyridium, in chemically pure condition, may be easily and quicklyobtained from aniline and diaminopyridine, as has already been pointedout.

.into pyridium, that is, the monohydrochloride, by means of distilledwater.

3. In reaction with distilled water, the dihydrochloride ofphenyl-azo-alpha-alpha-.

diaminopyridineinstantly splits 011' one molecule of hydrochloric acid,and is thereby converted into monohydrochloride ofphenylazo-alpha-alpha-diaminopyridine, that" is,

-pyrid-ium. The pyridium so produced is distinguished from pyridiumobtained in the ordinary way, in that it dissolves relatively 5' moreeasily in cold Water. In this way it becomes-possible to obtain verystrong and probably supersaturated solutions 01 pyridium, say 3%solutions, which are fairly stable, whereas, strong solutions ofpyridium (3%) obtained"without the'aid of dihydrochloride aredistinguishedby their excessive instability. They form very rapidly andeasily a sediment of pyridiuni.

4. addition the dihydrochloride may be used in substantially the samemanner as the 25 monohydrochloride, that is, in the treatment ofdiseases caused by bacterial infection, the procedure withdihydrochloride being substantially the same as that with themonohydrochlorides. The statements in regard to 30 structure are largelytheoretical and are not intended as limitations.

What is claimed as new'is 1. As an article of manufacture,phenyldiazo-alpha-alpha diaminopyridine dihydro- "chloride having thefollowing characteris- New York and State of New York, this 20th =5 clayof Sept, A. D. 1927.

lWAN OSTROMISLENSKY.

